JPS59130281A - Manufacture of thiazolidine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to new pharmaceutically effective 5-phenyl-thiazolidin-4-one derivatives and methods for their preparation. These compounds are useful in treating liver dysfunction.

The compound of the present invention has the general formula R2 [wherein R1 is a lower alkyl group, R2 is a lower alkyl group or an aralkyl group, and R3 is directly bonded to the thiazolizonone ring through a nitrogen atom]
, R4 N \R5 (wherein R4 and R5 are the same or different and are lower alkyl groups or hydroxyalkyl groups, or R
4 and R5 together with the nitrogen atom to which they are bonded represent a basic group having a saturated heterocycle of 4 to 6 carbon atoms]; is a pharmaceutically acceptable salt of

Lower alkyl and hydroxyalkyl groups are straight or branched and contain up to 6 carbon atoms. Aralkyl groups within the scope of the invention include aromatic rings, preferably benzene rings, and alkylene groups having up to 6 carbon atoms.

Ro is an alkyl group having up to 6 carbon atoms, sR2 is an alkyl group having up to 6 carbon atoms or benzyl: B3 is a basic group of the above general formula, and R4 and R5 are the same or different and have 6 carbon atoms. Preference is given to compounds of general formula (I) in which R4 and R5 together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring.

(L [Examples of alkyl groups include methyl group, ethyl group,
n-propyl group, isozolobyl group, n-butyl group, isobutyl group, n-pentyl group and n-hexyl group. A hydroxyalkyl group is a corresponding primary or secondary aliphatic alcohol group.

Among these advantageous compounds are compounds in which R1 is an ethyl group, R2 is a methyl or ethyl group and R3 is a piperidino or pyrrolidino group, and their salts with pharmaceutically acceptable acids.

The new compound according to the present invention is a compound having the general formula (wherein R0 and R2 have the same meanings as above and Y is a halogen atom) and a compound having the general formula %formula%() (wherein R4 and R5 have the same meanings as above). It can be produced by reacting with a compound having the same meaning).

This reaction is carried out in situ, i.e. in the chlorinated hydrocarbon used to prepare it, or intermediate (IV)
& After separation, it can be carried out in diethyl ether, dioxane or benzene at temperatures from 0 to 20°C. The reaction is generally complete in 4 to 20 hours, but in some cases it may be necessary to heat the mixture afterwards to reflux for 0.5 to 1 hour.

The starting material of the general formula (IV) is a compound having the general formula o-0R7 (in which R7 is a lower alkyl group) and a compound having the general formula % (in which R1 has the same meaning as above). is reacted in the presence of a basic catalyst to give a compound having the general formula (wherein R1 has the same meaning as above), and then the acidic 6-position is reacted with a suitable reactive ester such as an alkyl or alkylated or benzylated with a benzyl halide and then converted to the 5-alkaline earth salt in a suitable alkaline medium or reacted with free rodene, preferably bromine, in an inert medium.

Preferably a chlorinated hydrocarbon, such as carbon tetrachloride, is used as inert solvent. Bromination is elemental bromine or N-
It can be carried out using bromsuccinimide. Reaction times are usually about 1 to 2 at temperatures between about 50 and 80 degrees Celsius.
Time.

The compound of general formula (■) is also a new compound.

Introduction of the group R2 can be carried out at temperatures of about 60 to 100 DEG C., usually with the addition of a molar or excess amount of the acid acceptor, and in a polar solvent such as ethanol or isozolopanol. For the acid acceptor, use xylidine, triethylamine or potassium carbonate. Reaction time is about 1 to 5 hours.

The ring-forming condensation of compounds (Vl) and (■) is a United States patent, % 3,182.063 and 3,072,6
It is carried out by the method described in 53.

When compound (I) contains a basic amino group, it can be converted into a pharmaceutically acceptable salt by a conventional method.

For example, the free base is prepared with a pharmaceutically acceptable inorganic or organic acid.

The compounds of general formula (1) and their salts may be administered orally or by injection in admixture with conventionally used solid or liquid pharmaceutical diluents or carriers. As an injection medium,
It is advantageous to add additives that contain the usual additives for injection solutions, such as stabilizers, solubilizers or buffers. Formulations for oral administration may optionally contain flavoring and/or sweetening agents.

The dosage of the new compounds according to the invention will vary depending on the nature and severity of the disease to be treated. A single oral dose usually ranges from about 50 to 500 doses.

The following examples are intended to illustrate the invention.

Example 1 (Reference example) 6-methyl-5-ethyl-5-phenyl-4-oxo-
Δ2'-thiazolidine-ethyl acetate 1.2 g of sodium rings (0.05 mol) are dissolved in 150-g of anhydrous boiling hex-butanol to obtain sodium hex-butyrate.

14g of 6-methy2,α-5-phenyl-4-oxo-△-IF-7soI
Add ethyl acetate to this solution and then add 20-
A solution containing ethyl iodide 100- in absolute ethanol is added. Heat to reflux for 45 minutes to produce a yellow solution. After a further 45 minutes, all of the solvent mixture was removed under reduced pressure and the residue was dissolved in 0.5 liters of water and 100-
distributed between the ether and the ether. The ether phase is dried and distilled and the residue obtained is then distilled. As a highly viscous yellowish gelatin, boiling point 200 degrees C/1 rxx,
Hg-, 6-methyl-5-ethyl-5-phenyl-
4-Oxo-Δ2''-thiazolidine ethyl acetate is obtained.

The IR spectrum is 1712cIn-” (lactam ring)
, 1688cIrl-" (s, (1, I-unsaturated ester), 1570 an" (CH=C), 11
80cIn-1 (s, c-.

asymmetric), 1040 cm-' (m, c-o symmetric), 795CIn-1 (m, H-C=), 695cI
n-1 (m.

phenyl).

Analytical value 016H□9NO3S (molecular weight 305.39) Calculated value: C62, 96%; H6, 27%; N4.58%
; 810.50% Experimental value: 62.70%; 6
．． 29%; 4.75%; 10.29% The following compound is prepared in a similar manner.

3-Methyl-5-ethyl-5-phenyl-4-okyne-△2 h a-thiazolidine methyl acetate 6-methyl-5
-Ethyl-5-phenyl-4-oxo-△2・“-thiazolidine-butyl acetate and 3゜51′ethyl-5-phenyl-4-,,t=?so△2”-thiazolidine-butyl acetate used as starting material The compound is produced as follows.

10.6.9 (0.1 mol) of triethylamine 2
In a solution containing 101 nt of anhydrous benzene, 11.9
g (0.1 mol) of ethyl cyanoacetate and 18.2 g (0.1 mol) of ethyl cyanoacetate.
A mixture of α-mercazotophenyl methyl acetate (3 mol) was added immediately, and the reaction mixture was then stirred at room temperature for 18 hours. The reaction product gradually precipitates in the form of platelet crystals. This separates. Next, the remaining residue is evaporated to dryness, and the residue and crystals are re-condensed from benzene.

14.61 (>55.5% of theory) of 5-phenyl-4-oxo-△2''-thiazolidine-acetic acid ethylene. Melting point 177-178 degrees CO 3-phenyl-4-oxo-△2ja-thiazolidine-acetic acid n- Produced using a method similar to decyl.

In the case of a 0.1 molar batch, 21.0 g of a product with a theoretical value of 711 was obtained.
Dissolve 15,8,9 (0,06 mol) of 5-phenyl-4-oxo-Δ2''-thiazolidine-ethyl acetate in 96% ethanol at 67 degrees C0 and gently reflux.9
．． Stir with 1 g (0.66 mol) of potassium carbonate powder. Furthermore, it was heated externally and 7.6 g (
0.06 mol) dimethyl sulfate is fed. The reaction mixture was then heated to reflux for 1 hour, then ca.
Pour into 5 liters of hot water.

The product that separates is filtered off, dried and recrystallized from cyclohexane. 12.0,! i' (theoretical value 72) of 6-methyl-5-phenyl-4-oxo-Δ
21'2-Thiazolidine ethyl acetate is hot. Melting point 112
to 114 degrees C0 6-methyl-5-phenyl-4-oxo-△2. α-thiazolidine n-butyl acetate is prepared in a similar manner. 0
．． Using a batch of 0.35 mol, s, oy (theoretical value of 74
．． 8%) of the product. Melting point 98°C after recrystallization from ligroin.

For example, 6-ethyl-5-phenyl-4-oxo-Δ2·“-thiazolidine-acetate 1#n-butyl is obtained in a similar manner using diethylsulfnitrate.

Using 0.06 molar batch Y, yield 12.1 g (63.3% of theory), ether/petroleum ether (1:1)
, J: The melting point of the product after recrystallization is 84 degrees C8 Example 2 (
Reference example) 5-phenyl-3,5-dibenzyl-4-okine-△2
"-thiazolidine-ethyl acetate 10.59 (0.04 mol) of 5-phenyl-4-oxo-Δ2°"-thiazolidine-ethyl acetate 180-
12.14 g (0,088
mol) of anhydrous potassium carbonate powder. The reaction mixture is boiled and stirred constantly. 10.08 g] ] (0.08 mol) of benzyl chloride are added slowly and the reaction mixture is heated to vigorous reflux for 2 hours. Pour into 0.5 liters of hot water while still warm, separate the precipitated product, and take up in ethyl acetate/benzene (1:1). After removing the solvent mixture, the residue is triturated with ether and recrystallized from methanol. 8fi (42.4% of theoretical value) of 5-phenyl-6,5-dibenzyl-4-okine-△2・“-
Thiazolidine ethyl acetate. Melting point 154-156
degree 00 analysis value C2, H2, No3B (molecular weight 443.57) calculated value: C! 72.81%; H5,7Dchi; N3.3
6%; 87.37chi Experimental value: 73.10%;
5.69%; 3.16*; 7.73% Example 6 (
Reference example) 6-Methyl-5-phenyl-5-benzyl-4-oxo-△2・“-thiazolidine-ethyl acetate 8.319 (
0.03 mol) of 6-methyl-5-7ale-4-oxo-Δ2Ia-thiazolidine-ethyl acetate and 4.56
# (0,033 mol) of potassium carbonate (anhydrous, powder)
and are introduced into 120 liters of absolute ethanol. The reaction mixture is heated to reflux and 3.78.9 (0.05 mol) of benzyl chloride are added dropwise over the course of 1.5 hours. Next, half of the solvent is distilled off, and the residue is kneaded with hot water. It is then extracted with ethyl acetate and the extracted residue is kneaded with cyclohexane for several hours. Recrystallization from petroleum ether yields 6-methyl-5-phenyl-5-benzyl-4-oxo-Δ2"-thiazolidine ethyl acetate of 6.0 fl C (54.5% of K). Melting point 10.
5 to 107 degrees 00 Analysis value C21H21NO38 (molecular weight 367.47) Calculated value: c 68.63%; N 5.76%; N 3.
82%; S 8.73% Experimental value: 6B, 65chi;
5.57chi; 3.93chi; 9.01% cases
4 (Reference example) 6-Methyl-5-phenyl-5-(2-diethylaminoethyl)-4-okine-Δ2°0-thiazolidine Ethyl acetate 6-methyl-5-phenyl-4-oxo-Δ2°“-thiazolidine - React ethyl acetate and diethylaminoethyl chloride in a manner analogous to Example 6. The reaction mixture is added to hot water and then extracted with ethyl acetate. The extract is shaken out each time with 2N hydrochloric acid. The hydrochloric acid phase is Make alkaline with an aqueous solution of IJ (1N hydroxide) and separate the crude base Y into ether. Evaporate the ether solution, dissolve the residue in isopropanol and add oxalic acid to precipitate the product. Oxalate 7 Separate and recrystallize from isozolopanol.When using a 0.025 molar batch, 6.
5 g (27 theoretical) of 6-methyl-5-phenyl-
5-<2-diethylaminoethyl)-4-oxo-△2
°“-thiazolidine-ethyl acetate, melting point 126 to 128 degrees C8 Analysis value CzzH3oNzO18 (oxalate) (molecular weight 466
．． 56>Calculated value: c 56.64%; H6,49%
; N 6.00%; El 6.87% Experimental value:
56.53%; 6.27%; 6.04%:6.
58 example 5 6-ethyl-5-phenyl-5-N -hy< +) y
Starting from no-4-oxo-Δ2·“-thiazolidine-ethyl acetate 5-phenyl-4-okyne-Δ2·“-tiapridine ethyl acetate, alkylation is carried out analogously to that described in Example 1 with diethyl sulfate. 6-ethyl-5-phenyl-4-oxo-△"a-far IJ 119.5 to 120 degrees C9 42.2 g (0.15 mol) of 6-ethyl-5-phenyl-4-oxo- △2.0-thia tosujin-ethyl acetate is dissolved in 9 liters of anhydrous carbon tetrachloride. The solution is heated to reflux and 24 g (7.7 mg, 0.15 mol) of bromine is gently mixed.1. After 5 hours, the still dissolved aqueous bromide jFl is driven off with nitrogen. 6-Ethyl-
5-Bromine-5-phenyl-4-oxo-Δ2・0-thiaf Lysine ethyl acetate is not separated, but piperidine (
35.6m, 0.56 mol). Thereafter, the reaction mixture is further heated to reflux for 0.5 h. The giberidine hydrobromide is filtered off, the filtrate is evaporated to dryness and the residue is dissolved in 5 mg of hot inzolopanol. The separated crystals are collected and recrystallized from ethanol. 25.39
(Reason 5 45.2% of brass value: through 2 steps) 6-ethyl-5
-phenyl-5-N-piperidino-4-okineme 2.
"-thiazolidine ethyl acetate. Melting point 106 degrees C8 Analysis value 020H26N203B (molecular weight 374.52) Calculated value: c 64.14 yen; H7,00%; H7,
48chi; s8.5schi experimental value: 64.28%;
6.71%; 7.66%; 8.71-example
6 3-ethyl-5-phenyl-5-(methyl-β-hydroxyethylamino)-4-oxo-Δ2. (2-thiazolidine-ethyl acetate 3-ethyl-5-phenyl-4-oxo-Δ21a-thiazoline ethyl acetate, reacted with bromine in a manner analogous to that described in Example 5. The resulting 6-ethyl-5-deromu5 -Phenyl-4-oxo-Δ2#"-thiazoline-ethyl acetate is reacted with N-methyl-ethanolamine, and the reaction product is column chromatographed on silica del using 1 benzene/methanol (9:1). 8.5 g (0
, 1 mole of F-6, total of 28% of the theoretical value in two steps) 6-ethyl-5-
Phenyl-5-(methyl-β-hydroxy 2,α-ethylamino)-4-oxo-Δthiazolidine-ethyl acetate. Isopropanol/ether (2:1
) after recrystallization melting point 117 degrees 00 analysis (direct Cl8H24N204S (molecular weight 364.47) calculated value: c 59.54%; H6, 61%; H7,
81%; BB, 65% Experimental value: 59.32% 6
．． 64% 7,69 8.79 cases 7 3-methyl-5-phenyl-5-N-pipe IJ di/-4
-Oxo-△2・"-thiazolidine ethyl acetate side 6-methyl-5-phenyl-4-oxo-Δ2°"-thiazolidine ethyl acetate prepared by the method described in 1 was prepared in situ in a manner similar to that described in Example 5. Treat with piperidine. In a 0.05 molar batch brominated in this way, 8.2,? 3-Methyl-5- (45.6% of theory, through two steps)
Phenyl-5-N-piperidino-4-oxo-Δ2・0
-thiazolidine-ethyl acetate. Melting point after recrystallization from ethanol 176 to 174 degrees C8 Analysis value 019H24N203S (molecular weight 360.47) Calculated value: C63,54%; H6,61s; N7.8
1%; S8.82% Experimental value: 63.30%;
6.71%; 7.70%; 8.90%Example 8 3-Methyl-5-phenyl-5-N-pyrrolisino 4-
Oxo-△2・“-thia f IJ gin-ethyl acetate 28
N (0.1 mol) of 6-methyl-5-phenyl-4-oxo-△2-thia-lysine-ethyl acetate is brominated as described in Example 5. The carbon tetrachloride phase is distilled off under reduced pressure. The residue was recrystallized from cyclohexane. 25.1 g (
6-methyl-5-bromo-5- (69.4% of theory)
Phenyl-4-oxonola-thiazolidine ethyl acetate Z is obtained. Melts at 95 to 106 degrees C without decomposition.

Calculated analytical value: bromine 22.4% Experimental value: 22.0% Obtained 3-methyl-5-bromo-5-phenyl-4-
Oxo-△2・“-thiazolidine-ethyl acetate and pyrrolidine were prepared in ether at 0° C. in a manner analogous to that described in Example 5.
React with. The yield was (50% of theory in a 0.07 mol batch, 12.9) of 6-methyl-5-phenyl-5-
N-pyrrolidino-4-okyne-Δ2'-thiazolidine-ethyl acetate is obtained.

Melting point 95 degrees C after recrystallization from ethanol Example 9 3-Methyl-5-phenyl-5-diethylamino-4-
Oxo-Δ2・“-thiazolidine-ethyl acetate 10.7
g (0.03 mol) of 6-methyl-5-phenyl-5
-Bromo-4-okine-△2·'-thiazolidine-ethyl acetate' was dissolved in 125 ml of dry ether and at 8 to 10 degrees C in an ether solution of 4.4 # (0,06
mol) of diethylamine. The diethylamine hydrobromide formed is filtered off and the filtrate is evaporated to dryness. Recrystallize from residual isopropanol. Yield 3.3.9
' (62% of theory) and 3-methyl-5-phenyl-
5-diethylamino-4-oxo-Δ2'-thiazolidine ethyl acetate 9. Melting point 112 degrees C8 Analysis value C□8H24N203S (molecular weight 3.48.47)
Calculated value: c 62.04%; H6,94%; N
8.04chi; S 9.20% Experimental value: 62.12
%; 6.82%; 7.80%; 9.05%
Pharmaceutical comparative experiment example 10 Acute toxicity Acute toxicity of thiazolidone according to the present invention 21 to 26
Male mice weighing 11 (NMRI) are studied. Before the start of the experiment, the animals were fasted for 24 hours, but water was provided ad libitum.

There will be 4 animals for each treatment group. Dosage is increased by 2-fold. The test compound is suspended in 1% tragacanth and gum paste and administered orally via tube. The amount of liquid administered is 0.2
-/10. ! 9 weight.

Observe for a total of 7 days. Silymarin
in) 2-(2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)
Merck
Index page 1103] is used for standard storage. The measured LDbo values are shown in Table 1 below.

Table 1 Acute toxicity of thiazolidone according to the present invention in a 7-day mouse test 1 = 6-methyl-5-phenyl-5-N-piperidino-4-oxo-Δ2·“-ethyl thiazolicine acetate (Example 7) 2 = 3-Methyl-5-phenyl-5-N-pyrrolidino-
4-oxo-Δ2Ia-thiazolidine-ethyl acetate (Example 8) 6=6-methyl-5-ethyl-5-phenyl-4-oxo-Δ2·“-thiazolidine-ethyl acetate (Example 1) 4-6-ethyl-5 -Phenyl-5-N-pyrrolidino-
4-oxo-Δ2・0-thiazolidine-ethyl acetate (Example 6) 5-6-ethyl-5-phenyl-5-(methyl-β-hydroxyethylamino)-4-oxo-Δ2・“-thiazolidine-ethyl acetate (Example 6) Results As is clear from the results listed in Table 2 above, the 5
The acute toxicity of the species compounds is very low. Test compound location 1.
LD5o values of 2.4 and 5 exceed 1600~/#yx. The average toxicity of the standard substance silymarin is also 1,600 m
g/#v exceeds. LD for test compound/166
5o is approximately 1600 mg/匈.

Example 11 Hepatocellular oligodetoxification effect of thiazolidone according to the present invention on liver-injured rats caused by carbon tetrachloride. The duration of anesthesia after administration of sodium hexobarbital to rats with carbon-induced liver injury was measured. As for the compound having hepatocellular toxin detoxification effect, silymarin χ was used because it is a standard substance at the current state of the art.

N) The duration of anesthesia after administration of IJumhexobarbital is substantially determined by the rate of metabolism of this compound in the liver. In animals with carbon tetrachloride-induced liver damage, the duration of hexobarbital anesthesia is prolonged as a result of the effects of carbon tetrachloride-generated groups on the enzyme systems of the liver that break down foreign substances. These are expressed in the exchange action of the enzyme system and inhibit the decomposition of barbiturates (TC, Butler+ T, Pharm
acol, eXp, Therap-+311, 13
4/1961; T, F, 81ater+ Na
true.

56.209/1966; R.O.Reckn
agal.

Pharmacol R6v, 19.145/
1967).

Therefore, measuring the duration of anesthesia in animals with liver damage caused by carbon tetrachloride will reveal the functional state of the liver. (T, Ba1az SIH, C, Ori
celToxicol, appl, Pharmaco
l,,5,'387/1963;1't,Me
gillian, J. Pharmacol, ex
p, Th8rap, *see 144+331/1964). This method can be used to measure hepatoprotective substances because it limits the length of anesthesia for liver damage caused by carbon tetrachloride.

Method The experimental animals used are male boars (SIV50) weighing between 110 and 160 g. Standard feed? □ Give water freely. Each group has 10 to 12 animals.

Treatments with thiazolidone and silymarin according to the invention are in each case all for 4 days. Gum tragacanth suspension (2.d/100 g) is administered orally via tube daily. Carbon tetrachloride was administered on the second day of treatment, and the anesthesia time was measured on the fourth day.

There were two control groups, one group was given carbon tetrachloride and the other group was not given it. Both 2m//100. ! Give i' tragacanthime daily. Animals are fasted for 16 hours prior to carbon tetrachloride administration. Carbon tetrachloride is administered by diluting it in castor oil at a ratio of 1:50 (1-diluent/100.!
i + body weight). Control group animals that do not suffer from carbon tetrachloride liver damage receive only the above amount of castor oil while other groups receive carbon tetrachloride.

For anesthesia time measurements, freshly prepared sodium hexobarbital solution Y1701n was injected into the tail vein of the animal.
Inject intravenously at a rate of 1-7100 g over 1 minute to give a dose of 9//cg. The anesthesia time is from the end of the hexobarbital injection until the time when the animal recovers its orthotaxic and orthostatic reflexes.

Maintain normal animal body temperature with a heat lamp while anesthetized.

The average value and standard deviation are calculated from the measured values of each animal in each group. In order to examine the effects of thiazolidone and silymarin according to the present invention, the difference between the average anesthesia time of the liver damage control group and that of the control group without liver damage was set at 100, and the average anesthesia time of the liver damage substance administration group and the liver The difference from that of the unimpaired control group is calculated as a percentage of the above values. Significant differences between groups will be evaluated using the Student's method. The results of the comparative experiment are shown in Table 2 below.

As can be seen from Results Table 2, when liver damage is caused by carbon tetrachloride, 4
Anesthesia time is significantly longer than when there is no carbon chloride injury. Statistical calculations showed that there was a significant difference between the two control groups (p=<0.001) for all experiments.
).

As can be seen from Table 2, all of the five thiazolidones according to the present invention significantly reduced the anesthesia time in rats with carbon tetrachloride liver damage after 4 days of oral administration compared to the non-treated group with liver damage. let

The hepatocytotoxic detoxification effect of thiazolidone according to the present invention is shown in Table 2.
is highly significant as shown in the last column.

However, silymarin given at doses of 100 and 200 μ/ICg does not reduce anesthesia time in carbon tetrachloride liver impaired animals. In fact, although there is no significant difference, the anesthesia time of carbon tetrachloride liver-impaired animals is longer in the silymarin-treated group than in the untreated liver-impaired animal group.

The acute toxicity of the thiazolidones according to the present invention is in all cases LD5o of 1600 μ/kg or more, and the hepatocellular detoxification effect in the carbon tetrachloride test occurs at a dose substantially lower than that of silymarin, so there are five types. All the compounds will offer an excellent therapeutic spectrum.

Example 12 Hepatocytotoxic detoxification effect of thiazolidone according to the present invention on α-amanitine liver-injured mice In yet another animal experiment to test the hepatocytotoxic-detoxifying effect of the medicament, mouse liver damage caused by α-amanitine was used.

α-Amanitin χ It is extremely difficult to scale, so
The α-amanitin obtained for this experiment was limited to a very small amount, and the scope of the experiment was very limited.

Method Effect of α-amanitin on survival rate of liver-damaged mice/I
The effects of compounds 61 and /i64 were examined. Silymarin Y was again used as a standard substance in the hepatocellular toxin detoxification test of Hahn et al.
ung+9 18.697/1968) is used.

There were 25 animals in each group, and the test substance was administered daily for 6 days. Using a tube, add this to tragacantodem and add it to 'kO, 2d
/IC1 body weight. The untreated liver-impaired group will receive gum tragacanth daily for the same period.

0.5 m9/41 α-amanitin on each side is administered intraperitoneally on the second day of the experiment for all groups. The dose of α-amanitin is selected such that the mortality rate in untreated animals remains below 100 cm. Survival rates of animals in all experimental groups are recorded daily over a total of 14 days. Statistical comparison of survival rates was by Vierfelder's X2 test. Comparative values are shown in Table 3 below.

As can be seen from the results in Table 6, the two compounds of the present invention also exhibit excellent hepatocellular toxin detoxification activity in this test format.

When treated with compound/i61, α
- The survival rate of amanitin liver-impaired mice is increased by a significant difference of 0.001. Compound/164 increases animal survival by as much as 100%. This effect is highly statistically significant. The increased survival rate of α-amanitin liver-injured rats shown by Hahn cannot be confirmed in this experiment. Table 6. J: Clearly, silymarin does not increase survival.

Agent Asamura Hao 6 16 one

Claims (1)

[Claims] General formula (wherein R1 is a lower alkyl group, R2 is a lower alkyl group or an aralkyl group, and R3 is directly bonded to the thiazolidinone ring through a nitrogen atom, 5-phenyl-thiazolidine-4, which is lower alkyl or hydroxyalkyl or which together with the nitrogen atom to which they are attached form a saturated heterocycle having 4 to 6 carbon atoms A method for producing an -one derivative, comprising: a compound having the general formula (wherein R1 and R2 have the meanings as defined above, and Y is a halogen atom); R5 is as defined above).